Acute inhibition of oxidative drug metabolism by propoxyphene (Darvon)

Abstract

Propoxyphene is a potent inhibitor of the hepatic, microsomal mixed-function oxidases, acting in a manner similar to the prototype inhibitor of drug metabolism, SKF 525-A (β-diethylaminoethyl-2, 2-diphenylvalerate), which it resembles chemically. Propoxyphene ( K i = 4.6 ± 0.9 × 10 −5 M) and SKF 525-A ( K i = 4.0 ± 1.1 × 10 −6 M) inhibited competitively the activity of aminopyrine N-demethylase in washed microsomes from mouse liver. Both drugs were considerably weaker, noncompetitive inhibitors of the hydroxylation of aniline by microsomes. They manifested typical type I binding spectra to cytochrome P-450, propoxyphene binding approximately 15 per cent as avidly as SKF 525-A ( K s = 6.9 ± 0.5 × 10 −5 M for propoxyphene; 9.1 ± 1.8 × 10 −6 M for SKF 525-A). When propoxyphene and SKF 525-A were injected i.p. in equimolar (0.26 m-mole/kg) doses, both depressed the N-demethylation of aminopyrine and the hydroxylation of aniline by the 10, 000 g supernatant fraction of mouse liver removed 0.5 hr post-administration. Propoxyphene was 30–40 per cent as potent as SKF 525-A as an inhibitor of these activities. When potassium ferricyanide (50 μM) was added to suspensions of hepatic microsomes from animals pretreated with propoxyphene or SKF 525-A, the complexes formed between the drugs and cytochrome P-450 were destroyed. This same equimolar dose of propoxyphene and SKF 525-A prolonged hexobarbital sleeping time and zoxazolamine paralysis time, propoxyphene again being 30–40 per cent as potent as SKF 525-A in these tests. Chronically, propoxyphene increased the rate of its own metabolism as well as that of aminopyrine and aniline, and levels of cytochrome P-450 and microsomal protein. Propoxyphene thus seems to act in a manner very similar to that of SKF 525-A, acting as a potent inhibitor of microsomal drug metabolism when given acutely and as an inducer when given chronically.